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Differential gene expression in CD8(+) cells from HIV-1-infected subjects showing suppression of HIV replication.

ABSTRACT: CD8(+) cells from healthy HIV-1-infected individuals suppress human immunodeficiency virus (HIV) replication in infected cells by a non-cytotoxic mechanism. This activity is associated with the production of a soluble CD8(+) cell antiviral factor (CAF) that inhibits viral replication at the level of transcription. Strong CD8(+) cell non-cytotoxic anti-HIV responses (CNARs) correlate with an asymptomatic state and long-term survival of HIV-infected individuals. This antiviral activity is lost when the infected individual advances to disease. In attempts to define the gene(s) mediating CNAR we have evaluated differential gene expression between CD8(+) cells from infected subjects with high CNAR and CD8(+) cells from uninfected controls that lack this activity. The expression analysis, using the Affymetrix GeneChip Human Genome U133 Set, indicated that 18% of the genes were differentially expressed (DE) of which 9.2% were up-regulated. A total of 568 genes were up-regulated with a >2.0-fold difference in expression levels and a >50% concordance of difference call. Stringent selection criteria narrowed down the list to 52 up-regulated 'high confidence genes' (> or = 75% concordance). These genes function in a wide variety of cellular processes and include 13 associated with immunologic activity.

SUBMITTER: Martinez-Marino B

PROVIDER: S-EPMC1987396 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Differential gene expression in CD8(+) cells from HIV-1-infected subjects showing suppression of HIV replication.

Martinez-Mariño Beatriz B Foster Hillary H Hao Yanling Y Levy Jay A JA

Virology 20070122 1

CD8(+) cells from healthy HIV-1-infected individuals suppress human immunodeficiency virus (HIV) replication in infected cells by a non-cytotoxic mechanism. This activity is associated with the production of a soluble CD8(+) cell antiviral factor (CAF) that inhibits viral replication at the level of transcription. Strong CD8(+) cell non-cytotoxic anti-HIV responses (CNARs) correlate with an asymptomatic state and long-term survival of HIV-infected individuals. This antiviral activity is lost whe ...[more]

PMID: 17240414

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Project description:Goal: To compare the gene expression profiles from pediatric patients with each other, with those reported in adults and in those related to exosomes. Background: Suppression of human immunodeficiency virus (HIV) replication by CD8+ T-cells (CD8 suppression) contributes to survival in adults and children < 1 year. Soluble CD8 suppression can also be seen in some older children with AIDS. The factor responsible, CD8-derived antiviral factor (CAF), acts at the level of HIV RNA transcription. Differential gene expression techniques have been used to define the gene(s) mediating this phenomenon in adults. Recently, CAF has been linked to exosomes secreted by CD8+ T-cells. Objective: To compare the gene expression profiles from pediatric patients with each other, with those reported in adults and in those reportedly related to exosomes. Design/Methods: We used differential gene expression to study 3 older children with HIV infection, 1 who did demonstrate soluble CD-8 suppression and 2 who did not, and compared our results with those reported in 2 previous studies in adults and their relatedness to exosome components secreted by CD8+ T-cells. Results: 18 differentially expressed genes were also seen in 1 adult study (p=0.002, Ï2 test), and 38 such genes (p < 0.0001, Ï2 test) in a second adult study. In addition, two exosome components and some RNAâs related to exosomal proteins were also differentially expressed. Conclusions: In children with HIV infection, we found significant differentially expressed genes that correlated to those previously reported in 2 studies in adults. Our data also lends some support to the recent identification of CAF with exosomes secreted by CD8+ T-cells. Differential gene expression was used to study 3 older children with HIV infection, 1 who did demonstrate soluble CD-8 suppression and 2 who did not, and compared our results with those reported in 2 previous studies in adults and their relatedness to exosome components secreted by CD8+ T-cells. Three vertically-HIV-1-infected adolescent boys were studied. This study was approved by the Childrenâs Memorial Institutional Review Board. After informed consent was obtained, 20 - 40 ml of heparinized peripheral blood was collected in association with regularly scheduled, clinically-indicated blood sampling. Keywords: differential gene expression; soluble CD8 suppression; gene array; pediatric HIV infection; CD8-derived antiviral factor

Project description:Despite the suppression of viral replication induced by the highly active anti-retroviral therapy (HAART), an increased immune activation and inflammatory state persists in HIV-infected patients, contributing to lower treatment response and immune reconstitution, and development of non-AIDS conditions. The chronic activation and inflammation affect the functionality and differentiation of CD8+ T-cells, particularly reducing their cytotoxic capacity, which is critical in the control of HIV replication. Although previous studies have shown that HAART induce a partial immune reconstitution, its effect on CD8+ T-cells cytotoxic function, as well as its relationship with the inflammatory state, is yet to be defined. Here, we characterized the functional profile of polyclonal and HIV-specific CD8+ T cells, based on the expression of cell activation and differentiation markers, in individuals chronically infected with HIV, under HAART. Compared with seronegative controls, CD8+ T-cells from patients on HAART exhibited a low degranulation capacity (surface expression of CD107a), with consequent low secreted levels and high intracellular expression of granzyme B and perforin. This degranulation defect was particularly observed in those cells expressing the activation marker HLA-DR, which were further characterized as effector memory cells with high expression of CD57. The expression of CD107a, but not of granzyme B and perforin, in CD8+ T-cells from HIV-infected patients on HAART reached levels similar to those in seronegative controls when the treatment duration was higher than 25 months. In addition, the expression of CD107a was negatively correlated with the expression of exhaustion markers on CD8+ T-cells and the plasma inflammatory molecule sCD14. Thus, despite HAART-induced viral suppression, CD8+ T-cells from HIV-infected patients have an alteration in their cytotoxic program. This defect is associated with the cellular activation, differentiation and exhaustion state, as well as with the inflammation levels, and can be partially recovered with a long and continuous treatment.

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Differential gene expression in CD8(+) cells from HIV-1-infected subjects showing suppression of HIV replication.

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Differential gene expression in CD8(+) cells from HIV-1-infected subjects showing suppression of HIV replication.

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